Synthetic Reader-Actuators Targeted to Polycomb-Silenced Genes Block Triple-Negative Breast Cancer Proliferation and Invasion
Copyright 2023, Mary Ann Liebert, Inc., publishers..
Scientists have used pharmacological inhibitors of polycomb proteins to restore the expression of tumor suppressor genes and stop cancer proliferation and invasion. A major limitation of this approach is that key transcriptional activators, such as TP53 and BAF SWI/SNF, are often mutated in cancer. Poor clinical results for polycomb-targeting therapies in solid cancers, including triple-negative breast cancer (TNBC), could discourage the further development of epigenetic monotherapies. Here, we performed epigenome actuation with a synthetic reader-actuator (SRA) that binds trimethylated histone H3 lysine 27 in polycomb chromatin and modulates core transcriptional activators. In SRA-expressing TNBC BT-549 cells, 122 genes become upregulated ≥2-fold, including the genes involved in cell death, cell cycle arrest, and migration inhibition. The SRA-expressing spheroids showed reduced size in Matrigel and loss of invasion. Therefore, targeting Mediator-recruiting regulators to silenced chromatin can activate tumor suppressors and stimulate anti-cancer phenotypes, and further development of robust gene regulators might benefit TNBC patients.
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:2 |
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| Enthalten in: |
GEN biotechnology - 2(2023), 4 vom: 01. Aug., Seite 301-316 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hong, Lauren [VerfasserIn] |
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Date Revised 04.12.2023 published: Print-Electronic UpdateOf: bioRxiv. 2023 Jan 23;:. - PMID 36747762 Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1089/genbio.2023.0020 |
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| funding: |
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NLM364202483 |
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| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a Copyright 2023, Mary Ann Liebert, Inc., publishers. | ||
| 520 | |a Scientists have used pharmacological inhibitors of polycomb proteins to restore the expression of tumor suppressor genes and stop cancer proliferation and invasion. A major limitation of this approach is that key transcriptional activators, such as TP53 and BAF SWI/SNF, are often mutated in cancer. Poor clinical results for polycomb-targeting therapies in solid cancers, including triple-negative breast cancer (TNBC), could discourage the further development of epigenetic monotherapies. Here, we performed epigenome actuation with a synthetic reader-actuator (SRA) that binds trimethylated histone H3 lysine 27 in polycomb chromatin and modulates core transcriptional activators. In SRA-expressing TNBC BT-549 cells, 122 genes become upregulated ≥2-fold, including the genes involved in cell death, cell cycle arrest, and migration inhibition. The SRA-expressing spheroids showed reduced size in Matrigel and loss of invasion. Therefore, targeting Mediator-recruiting regulators to silenced chromatin can activate tumor suppressors and stimulate anti-cancer phenotypes, and further development of robust gene regulators might benefit TNBC patients | ||
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| 700 | 1 | |a Shields, Cara E |e verfasserin |4 aut | |
| 700 | 1 | |a Haynes, Karmella A |e verfasserin |4 aut | |
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